Download Spanish Menopause Society position statement: use of tibolone in

Menopause: The Journal of The North American Menopause Society
Vol. 20, No. 7, pp. 00/00
DOI: 10.1097/gme.0b013e31827b18c5
* 2013 by The North American Menopause Society
Spanish Menopause Society position statement: use of tibolone
in postmenopausal women
Nicolás Mendoza, MD, PhD,1 Pedro Abad, MD, PhD,2 Francesc Baró, MD, PhD,3
Ma Jesús Cancelo, MD, PhD,4 Plácido Llaneza, MD, PhD,5 Montserrat Manubens, MD, PhD,6
Francisco Quereda, MD, PhD,7 and Rafael Sánchez-Borrego, MD, PhD8
Abstract
Tibolone is a drug with complex tissue-specific action that exhibits a combination of estrogenic, progestogenic,
and slight androgenic activity. Its variable profile explains its clinical effects, depending on the target tissue where it
is metabolized, its metabolites’ affinity for and potency in hormone receptors, and probable enzymatic activity
modulation. In recent reviews and clinical trials, the effectiveness of tibolone in alleviating different hot flush
menopause symptoms, mainly in mood and sexuality disorders, has been noted. In Spain, tibolone is the most
prescribed hormonal treatment, and one of the most common complaints among postmenopausal women is change
in sexual drive. For such reason, a panel of experts from the Spanish Menopause Society met to develop usage
recommendations based on the best evidence available.
Key Words: Tibolone Y Postmenopausal Y Hormone therapy.
T
ibolone was initially developed for the treatment of
osteoporosis, but its benefits have been recognized to
be extended to other organs and systems, such that
this drug is currently approved for the treatment of postmenopausal women in more than 70 countries. Although the
effectiveness of tibolone in alleviating hot flushes seems
similar to that of low-dose hormone therapy (HT), its specific
pharmacological profile adds some advantage over other HTs
in women with other symptoms.
Tibolone is a synthetic molecule derived from the basic
nucleus of cyclopentanoperhydrophenanthrene, with a structure related to gestagen norethynodrel. The unique configuration of this drug determines its pharmacokinetics, which, in
addition to its physicochemical characteristics, permits its oral
administration as a single daily dose. After being absorbed,
tibolone is metabolized differently in various target tissues,
yielding diverse acting metabolites, primarily 3>-OH-tibolone,
3A-OH-tibolone, and the isomer $4 (the latter in the endome-
Received September 26, 2012; revised and accepted October 25, 2012.
From the 1Department of Obstetrics and Gynecology, University of Granada,
Granada, Spain; 2Hospital Torrecardenas, Almerı́a, Spain; 3Hospital Vall
d’Hebron, University of Barcelona, Barcelona, Spain; 4Hospital de
Guadalajara, University of Alcalá, Guadalajara, Spain; 5Asturias Central
University Hospital, University of Oviedo, Oviedo, Spain; 6Instituto
Dexeus, Barcelona, Spain; 7Hospital San Juan, Alicante, Universidad
Miguel Hernández, Alicante, Spain; and 8Clı́nica Diatros, Barcelona,
Spain.
Funding/support: None reported.
Financial disclosure/conflicts of interest: None reported.
Address correspondence to: Nicolas Mendoza, MD, PhD, Maestro Montero, 21, 18004 Granada, Spain. E-mail: [email protected]
trium). These metabolites interact and variably potentiate
estrogen, progesterone, and androgen receptors, as shown in
Table 1, leading to its recognition as a selective tissue estrogenic activity regulator.1 Furthermore, in vitro studies and
other enzymatic activities have suggested that tibolone could
prevent cellular proliferation, which could be of specific
importance in breast tissue.2
EFFECTIVENESS
Vasomotor symptoms
The effectiveness of tibolone in alleviating vasomotor disorders has been compared with that of low-dose HT; as such, a
recent review places this drug behind conventional HT in the
reduction of the frequency of hot flushes. Compared with
placebo, tibolone was more effective in relieving the frequency of vasomotor symptoms (two randomized clinical
trials [RCTs], n = 847; odds ratio, 0.42; 95% CI, 0.25-0.69),
although only tibolone 2.5 mg/day was significantly better
than placebo. Compared with HT, tibolone was less effective
in relieving the frequency of vasomotor symptoms (two RCTs,
n = 545; odds ratio, 4.16; 95% CI, 1.50-11.58).3
In most clinical trials supporting this meta-analysis, it is
striking that no significant differences in the improvement of
these symptoms have been found between tibolone and HT. In
another review from 2010, no differences were observed
between conventional HT and tibolone.4
Data from a recent RCT confirmed that tibolone is significantly more effective than placebo and as effective as lowdose continuous-combined estradiol (E2)/norethisterone acetate (NETA) in reducing vasomotor symptoms.5,6 An RCT of
Menopause, Vol. 20, No. 7, 2013
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MENDOZA ET AL
TABLE 1. Affinities of tibolone and its metabolites for
steroid receptors
Steroid receptor
Steroid
Tibolone
Isomer $4
3>-OHYderived
3A-OHYderived
Estrogen
Progesterone
Androgen
Weak
None
Weak
Weak
Weak
Moderate
None
None
Weak
Moderate
None
None
two doses of tibolone (1.25 and 2.5 mg) for the treatment of
moderate to severe vasomotor symptoms and of symptoms
associated with vaginal atrophy confirmed the usefulness even
of low doses. This RCT also found that both doses of tibolone
significantly reduced the severity of flushes at 12 weeks (mean
changes in severity scores: j1.7 with tibolone 2.5 mg vs j0.9
with tibolone 1.25 mg vs j0.3 with placebo; P G 0.001 for both
tibolone 2.5 mg and tibolone 1.25 mg vs placebo).7
In a review of our data (some included in the review of
Mendoza et al8,9) on women with moderate to severe vasomotor symptoms, tibolone was as good as estrogen therapy
(93.1% vs 96.1%).
Quality of life
Not only does it seem that tibolone is not inferior to conventional HT in the improvement of menopausal symptoms,
but there are findings suggesting that global positive effects
could be greater with tibolone, especially on nonvasomotor
menopausal symptoms. An RCT that compared tibolone, 17Aestradiol, and placebo in a group of women with surgical
menopause found differences in favor of tibolone in the alleviation of symptoms other than vasomotor symptoms (including nervousness, sleep disturbances, difficulty concentrating,
sensation of fatigue or loss of energy, disinterest, crying, and
migraines).10
In our study, tibolone was better than estrogen therapy in
alleviating mood and sexuality disorders, but it did not reach
statistical significance (76.5% vs 42.8%, P = 0.08; and 91% vs
47%, P = 0.056, respectively).9
One possible explanation for these findings is that tibolone
normalizes A-endorphin levels, behavioral changes, and mood
disorders caused by the combined activity of its metabolites
on the central nervous system: that of the isomer $4 binding
with receptors for androgens and those of the derived 3>hydroxy and 3A-hydroxy forms binding with receptors for
estrogens.
Precisely because there are symptoms other than hot flushes
that impact quality of life and because the presentation of
climacteric syndrome is influenced by notable biological and
cultural aspects, a group of experts from Oceania and East
Asia has presented a position on the use of tibolone, arguing
that this medication is a treatment that offers additional possibilities to those offered by conventional HT; this position
came from a geographic area where the main medical consultations were related to insomnia.6 Along these lines, the
international consensus of 2005 compares tibolone with con-
2
Menopause, Vol. 20, No. 7, 2013
ventional HT in effectiveness against vasomotor symptoms,
but the former is given a superior position in the overall
improvement of quality of life. This document points out the
action of tibolone against sleep, sexuality, and mood disorders; combined with the fact that bleeding is scarce and
breast discomfort is lesser with tibolone, these findings indicate that tibolone may be the treatment of choice for women
who present with mood changes, apart from vasomotor symptoms and musculoskeletal pain.5
Although scarcity of bleeding with tibolone has been suggested as one of the factors that contribute to its users feeling
better than those who take conventional HT (bleeding with
tibolone: 18.3% vs 33.1% at 1-3 mo, P G 0.001; and 11% vs
19% at 7-9 mo, P G 0.05, with respect to transdermal E2/
NETA), there are symptoms other than hot flushes that affect
quality of life and could be better alleviated by tibolone,
probably mediated by its slight androgenic effect.11
Sexuality
Tibolone reduces vaginal dryness and symptoms resulting
from this condition (dyspareunia, pain, itching, or vaginal lubrication) similarly to conventional HT.11 In addition, tibolone has
a positive effect on other aspects of sexuality, making it comparable to the combination of HT with androgens (Table 2).12
Admittedly, the beneficial effects of therapies aiming to
improve feminine sexuality are modest, and RCTs of tibolone
compared with testosterone have not been performed. Instead,
RCTs that use specific scales for evaluating sexualityV
primarily the Female Sexual Function Index scaleVdemonstrate
overall improvement for any HT versus placebo but offer
better outcomes for tibolone within specific parameters such
as desire, orgasms, frequency of intercourse, responsiveness,
arousal, or satisfaction.13<16
In the Livial International Study in sexual Arousal disorders
(LISA), which is the main RCT conducted on sexuality with
tibolone, the total Female Sexual Function Index score and the
subscores for arousal, desire, and satisfaction showed a significant increase from baseline (P G 0.001) for both tibolone
and E2/NETA (32% vs 26% per protocol analysis, P = 0.025
between groups).13
Tibolone has a significantly better tolerability profile than
transdermal E2/NETA, as measured by vaginal bleeding,
breast pain, and treatment continuation: bleeding/spotting
events (16% vs 56% at weeks 1-12, P G 0.001; 12% vs 51% at
TABLE 2. Aspects of sexuality in which improvement has been
observed with tibolone
Relative to a placebo:
& Increase in blood flow and vaginal lubrication
& Increase in sexual fantasies, sexual desire, and arousal
& No differences in intercourse frequency, sexual activity without penetration,
or initiation or rejection of sexual activity
& Increase in plasma testosterone and sex hormoneYbinding globulin
Relative to hormone therapy:
& Increase in desire, orgasms, intercourse frequency, responsiveness, arousal,
or satisfaction
& Increase in plasma testosterone and decrease in sex hormoneYbinding globulin
* 2013 The North American Menopause Society
SMS POSITION ON USE OF TIBOLONE
weeks 13 and 24, P G 0.001), vaginal hemorrhage (11% vs
0%, P G 0.001), and breast signs and symptoms (11% vs 4%,
P = 0.015).17
Cardiovascular effects
Tibolone exhibits heterogeneous action on lipid profile but
generally has properties that could be considered antiatherogenic.
Although tibolone reduces high-density lipoprotein cholesterol, the most important of its lipid effects, in contrast to
estrogen, is a marked reduction in triglycerides, which constitute an independent risk factor for insulin resistance and
cardiovascular disease.18
In addition to these lipid-based mechanisms, several actions
of tibolone for cardiovascular protection have been proposed.
This drug reduces the concentration of lipoprotein(a), an agent
that is both atherogenic and thrombotic19; in addition, it does
not modify the levels of C-reactive protein.20 Its endothelial
activity is similar to that of estrogen: in experimental animal
studies, a reduction in the progression of atherogenic plaques
and endothelial damage, independent of lipid plasma levels
and probably mediated by nitric oxide, was observed.21<23
Regarding carbohydrate metabolism, in women with and
without diabetes mellitus, it has been observed that tibolone
does not change the blood levels of glucose, insulin, C-peptide,
or glycosylated hemoglobin, nor does it induce changes in oral
glucose tolerance.24
However, the Long-term Intervention on Fracture with
Tibolone (LIFT) study, a trial directed at evaluating the ability
to prevent fractures, had to be stopped early due to the
increased risk of stroke in women treated with tibolone (relative hazard, 2.19; 95% CI, 1.14-4.23; P = 0.02). Nevertheless, these women did not present an increased risk of
coronary heart disease or venous thromboembolism (VTE).
Perhaps age could be a determining factor in this finding, as
the average age of women exceeded 68 years. Although the
differences in absolute risk between groups did not reach
statistical significance and a greater thrombotic or coronary
risk was not recognized, the authors do not recommend
beginning treatment with tibolone in women older than 60
years who present an increased risk for stroke.25
The Osteoporosis Prevention and Arterial effects of tiboLone
(OPAL) trial reported that both tibolone and the combination of
conjugated equine estrogens (CEE) and medroxyprogesterone
acetate (MPA) were associated with the progression of carotid
intima-media thickness compared with placebo. The differences
from placebo (0.0042 mm/y for tibolone and 0.0039 mm/y for
CEE/MPA) were statistically significant (P = 0.03 and P =
0.04, respectively). However, this interpretation is questionable owing to inexplicable differences in results between
the European women and the American women in the trial.26
Subsequent comments on the trial reported that OPAL shows
that neither tibolone nor CEE/MPA has beneficial effects on
atherosclerosis, but neither were they harmful.18
In an RCT with placebo in a group of 100 healthy postmenopausal women younger than 65 years, tibolone did not
affect the resistance of small-caliber cerebral arteries.27
Finally, in other cohort studies or in RCTs in which the
objective was not the consideration of cardiovascular events,
no more myocardial infarction or stroke was observed with
tibolone, perhaps because the age of the women studied was
closer to the age at natural menopause.28
Skeletal effects
Tibolone produces a direct agonistic effect on estrogen
receptor, leading to increased bone mineral density (BMD),
reduction of the biochemical markers of bone resorption to
premenopausal values, and reduced risk of vertebral and nonvertebral fractures. The lumbar spine BMD increase described
at around 2 years of tibolone treatment varies between 3.8%
and 12%. In the Study of Tibolone’s Effects on osteoPenia
(STEP), significant increases in BMD were observed versus
raloxifene (3.8% vs 2.1% in the lumbar spine, P G 0.001; 1.26% vs
0.44% in the hip, P G 0.005).29
In the LIFT study, tibolone reduced the risk of both vertebral and nonvertebral fractures compared with placebo (43%
and 26%, respectively).20 The risk reduction of vertebral and
nonvertebral fractures was 8.6 and 6.9 per 1,000 patients/year,
respectively (relative risk [RR], 0.55; 95% CI, 0.41-0.74; P G
0.001; and RR, 0.74; 95% CI, 0.58-0.93; P = 0.001, respectively). These benefits have been noted in postmenopausal
women of any age, independent of whether menopause was
natural or surgical, and even in women with a history of breast
cancer.30<32
SAFETY
Although a recent review suggests that tibolone may not be
a good choice for long-term use, especially in women older
than 65 years, available data on the long-term safety of tibolone are satisfactory, specifically when tibolone is used in
healthy early postmenopausal women with no personal history
of breast cancer.33
Endometrium
Tibolone does not produce an estrogenic effect on the
endometrium owing to the local metabolism of the isomer $4,
which stimulates progesterone receptors. Thus, it decreases
bleeding, and risks of endometrial hyperplasia and adenocarcinoma in clinical trials were similar to those with placebo.34
In general, bleeding with tibolone is not very frequent and
typically presents in young women during the first 3 months
of treatment, when endogenous estrogen is still secreted.
As previous studies have described, in cases of polyps, fibroids, or atrophy in bleeding, acting in the same manner
by which abnormal uterine bleeding would be managed is
recommended.35<37
In the Million Women Study, an increase in endometrial
cancers was described in women treated with tibolone.
Besides the widely criticized shortcomings in the design of
this study, it should be noted that women treated with tibolone
had previously received estrogen treatment without gestagenic
opposition, which placed them at an increased risk for endometrial adenocarcinoma before the start of tibolone use.38
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MENDOZA ET AL
In the Tibolone Histology of the Endometrium and Breast
Endpoint Study (THEBES), which is an RCT on endometrial
safety with tibolone and CEE/MPA in 3,224 women, those
treated with tibolone did not present endometrial cancer or
hyperplasia, and ultrasonographic endometrial thickness was
not greater than that in the CEE/MPA group, additionally
indicating better tolerance of tibolone compared with women
treated with CEE/MPA.28
These results are consistent with those of the OPAL study,
the secondary objective of which was to measure endometrial
safety without recording greater endometrial pathology versus
placebo.26
Breast
In experimental animal studies or in vitro culture studies,
tibolone has shown an ability to inhibit the conversion of
estrone into E2 in breast tissue and the appearance of chemically induced tumors, to reduce the rate of proliferation, and to
increase the differentiation of epithelial mammary cells,
increasing apoptosis phenomena.39
Moreover, the breast pain/tenderness observed in women
treated with tibolone has been lower than that in women
treated with other HTs (3.2% vs 9.8% with transdermal E2/
NETA, P G 0.001).11 These results are similar to the result
described in THEBESVless breast pain in the tibolone group
than in the CEE/MPA group (4.3% vs 12.7%, P G 0.001).28
Some observational studies have reported that tibolone
does not increase mammographic density.40,41 Although an
increased risk of breast cancer was recorded among tibolone
users (RR, 1.45; 95% CI, 1.25-1.68; P G 0.0001) in the Million Women Study, this finding has not been verified in other
series.42 On the contrary, in the LIFT study, a decrease in the
risk of breast cancer was observed in the group treated with
tibolone in comparison with the placebo group (relative hazard, 0.32; 95% CI, 0.13-0.80; P = 0.02).20
Owing to generally positive results observed in the breast,43
the Livial Intervention following Breast cancer; Efficacy,
Recurrence, And Tolerability Endpoints (LIBERATE) study
was designed to compare the effectiveness and safety of tibolone against placebo in the treatment of vasomotor symptoms
among 3,148 women who had overcome the disease. After an
average follow-up of 3 years, 237 (15%) of 1,156 women using
tibolone experienced a recurrence of breast cancer, in comparison with 138 (11.4%) of 1,213 women in the placebo group
(hazard ratio, 1.40; 95% CI, 1.1-1.79); for this, the study was
halted 6 months before the planned date.44
Consequently, although tibolone alleviates vasomotor
symptoms and improves BMD, the use of this medication is
not recommended for women with a history of breast cancer.
Other cancers
There was no evidence that tibolone had detrimental effects
on the progression, free survival, and overall survival of patients with epithelial ovarian cancer.45
In the LIFT study, a decreased risk of colon cancer with
tibolone, compared with placebo, was observed (relative
hazard, 0.31; 95% CI, 0.10-0.96; P = 0.04).20
4
Menopause, Vol. 20, No. 7, 2013
Hemostasis
Strictly speaking, research on the parameters implied in
hemostasis is still unclear, but most investigations examining
the effects of tibolone agree that this drug does not increase
the risk of thrombosis.
A significant decline in fibrinogen and factor VIIa and a
rise in D-dimer and fibrin degradation products were detected
after 24 weeks of tibolone treatment.46 Moreover, a higher
activated protein C resistance ratio observed in women undergoing tibolone treatment47 may translate into a corresponding
low risk of deep vein thrombosis, as is also indicated by
existing clinical data.48<50
However, the LIFT study had to be halted when an increase
in stroke was observed in women undergoing treatment with
tibolone. If we accept that the procoagulant effect of oral HT
is related to the first-pass liver metabolism of the estrogenic
component, tibolone could be predicted to act this way.
However, its hemostatic effects are more androgenic than
estrogenic. Moreover, in the LIFT study, not a single thrombotic or coronary event was recorded, and it has been suggested that the increase in stroke could be related to the age of
the women (mean age, 68 y) or to the presence of other risk
factors (smoking, hypertension, etc).20
Studies subsequent to the LIFT study that have compared
the hemostatic changes occurring in women taking conventional HT, tibolone, or raloxifene show that women treated
with tibolone exhibit a pronounced decline in factor VII, a
smaller reduction in antithrombin and protein C, and even an
increase in other coagulation inhibitors.51,52
Consequently, the new research seems to corroborate the
idea that tibolone behaves hemostatically differently from oral
HT, with its slight androgenic properties predominating such
that its use has not been associated with an increase in the risk
of deep vein thrombosis in postmenopausal women.
Tibolone is a valuable and safe treatment option for healthy
early postmenopausal women with climacteric complaints and
might be preferable to conventional HT for women with surgical menopause and for those with intact uterus. However, in
women older than 65 years or in patients with breast cancer,
available data on the safety of tibolone are of concern owing
to the increased risk of stroke in a separate RCT and the
recurrence of breast cancer, respectively.
DISCUSSION
There are several reasons for elaborating a position on
tibolone in Spain: (1) this medicine has been the most widely
used HT for two decades; (2) it continues to be widely prescribed; and (3) it has suffered the least decrease in sales after
the publication of the Women’s Health Initiative study.53,54
Although the effectiveness of tibolone has been equated
with that of low-dose HT, its unique pharmacological profile
gives it some advantage over any of the HTs available for
women with symptoms other than hot flushes. The advantages
of tibolone over conventional HTs stated in the latest guidelines of the International Menopause Society include a more
* 2013 The North American Menopause Society
SMS POSITION ON USE OF TIBOLONE
effective alleviation of mood disorders and female sexual
disorders.5
In fact, in Spain, sexual disorder is one of the major concerns among postmenopausal women, making tibolone an
ideal treatment.55 The data that we use indicate that sexuality
disorders are brought up in most consults of postmenopausal
Spanish womenVsometimes in an obvious way and many
other times indirectly12Vand that the effectiveness of tibolone
could be comparable to that of the combined use of HT and
androgens.56 Sexuality is also a frequent complaint elsewhere
and clearly alters quality of life, so our recommendation can
be extended to other countries.57
Along the same lines, tibolone can treat women with surgical menopause better than conventional HT does because
tibolone can alleviate the effects of the deficit of other nonestrogen hormones. In an RCT performed in Spain in which
tibolone and transdermal 17A-estradiol were administered in
women with surgical menopause, differences in favor of
tibolone were found in the alleviation of nonvasomotor
symptoms such as nervousness, sleep disturbances, difficulty
concentrating, sensation of fatigue or loss of energy, disinterest, crying, and migraines. The improvement in sexualityrelated symptoms was higher in women taking tibolone than
in women taking placebo, with similar percentages of compliance and adverse effects.9
TABLE 3. Summary of the recommendations of the Spanish
Menopause Society
Recommendation
Level of
evidence
Tibolone is comparable to a low-dose HT in alleviating
2B
vasomotor symptoms.
When other symptoms predominate (insomnia, nervousness,
2C
disinterest, fatigue, and loss of concentration), the specific
profile of the clinical effects of tibolone can make a good
option.
Tibolone is indicated for women with androgenic deficit
2C
syndrome. Tibolone has shown itself to be superior to
conventional HT in women with surgical menopause.
Tibolone can be an alternative to conventional HT for the
2B
treatment of postmenopausal women with sexuality changes.
Tibolone reduces bone turnover, increases BMD, and reduces the
2A
risk of vertebral and nonvertebral fractures.
Tibolone shows beneficial effects on certain surrogate markers of
2B
cardiovascular disease, specifically in the reduction of
triglycerides. The use of tibolone is not recommended for the
primary or secondary prevention of cardiovascular disease.
Beginning treatment with tibolone in women older than 60 y who
2B
present risk factors for stroke is not advised.
Tibolone has been associated with an increased risk of venous
2B
thromboembolism less than that associated with oral HT.
Tibolone seems to be safe in its action on the endometrium.
2A
Tibolone does not increase breast density or mastalgia among
2C
postmenopausal woman.
The use of tibolone is not recommended for women with a
2A
history of breast cancer owing to an increased risk of
recurrence.
Levels of evidence: 1A, strong recommendation, evidence of high quality; 1B,
strong recommendation, evidence of moderate quality; 1C, strong recommendation, evidence of low quality; 2A, weak recommendation, evidence of
high quality; 2B, weak recommendation, evidence of moderate quality; 2C,
weak recommendation, evidence of low quality.
HT, hormone therapy; BMD, bone mineral density.
Moreover, safety information on hemostasis is available;
this will be included in the technical record for tibolone, primarily based on data extracted from a British case-control
study.58 The Spanish Agency of Medicines and Healthcare
Products has issued a report showing that the risk of VTE
associated with tibolone use is lower than the risk of VTE
associated with oral HT use.59 However, these data are very
limited such that they do not exclude the possibility of a small
risk of VTE among women taking tibolone in comparison
with women not taking this medication.
Lastly, in Spain, tibolone is not indicated for the prevention
of osteoporosis among asymptomatic women. However, in
several other member states of the European Union, it is
authorized for the prevention of osteoporosis among postmenopausal women who face the risk of fractures and who
cannot tolerate the use of other antiosteoporotic medications
or for whom the use of other antiosteoporotic medications is
contraindicated.
CONCLUSIONS
The effectiveness of tibolone has been equated with that of
low-dose HT, but its unique pharmacological profile gives it
an advantage over any of the HTs available for women with
mood disorders or sexual disorders (two of the major concerns
among Spanish postmenopausal women), making tibolone an
ideal treatment. Its effectiveness seems to be comparable to
that of the combined use of HT and androgens. From the point
of view of safety, the risk of VTE associated with tibolone use
is lower than that associated with oral HT use.
LIST OF RECOMMENDATIONS
The Spanish Menopause Society considers it appropriate to
develop its own recommendations based on the Grading of
Recommendations Assessment, Development, and Evaluation
(GRADE) system60 to elaborate clinical practice guidelines
and to classify quality of evidence and strength of recommendations (Table 3).
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